Sustained-Release Sunitinib Malate for Neovascular AMD

This durable agent has the potential to reduce treatment burden.

New Pathways in Retinal Drug Delivery

Graybug Vision’s GB-102 (sustained-release sunitinib malate) aims to improve the treatment burden of patients diagnosed with neovascular age-related macular degeneration (nAMD). Current standard of care includes frequent anti-vascular endothelial growth factor (anti-VEGF) injections. Due to frequent clinic visits and injections, the treatment burden leads to poor visual acuity outcomes in the real world.1 GB-102 was developed to reduce treatment burden by having a treatment that can maintain efficacy for up to 6 months.

GB-102 is formulated as an injectable, intravitreal poly lactic-co-glycolic acid (PLGA) that aggregates to form a depot, which then biodegrades over time to lactic acid and glycolic acid (Figure 1). The controlled sunitinib release is intended for biannual injection for patients with nAMD. All currently available nAMD therapies (aflibercept, brolucizumab, ranibizumab, and off-label bevacizumab) target VEGF-A ligand to prevent its binding to the extracellular VEGF receptors (VEGFR)-1 and -2. In contrast, sunitinib malate’s mechanism of action inhibits multiple intracellular tyrosine kinases (RTKs), ultimately producing an inhibitory effect on VEGFR-1, -2, and -3 (Figure 2). Sunitinib also inhibits platelet-derived growth factor receptors A and B, the stem cell growth factor receptor KIT, colony stimulating factor receptor 1, and the fms-related tyrosine kinase receptor FLT3. With the wide array of target effects, sunitinib malate has previously been approved as an oral agent for solid tumors such as renal cell carcinoma and pancreatic neuroendocrine tumors and shows potential to subdue neovascularization from AMD by inhibiting all VEGFRs.

Figure 1. GB-102 is a depot of PLGA microparticles containing sunitinib.

Figure 2. Sunitinib malate is a potent pan-VEGF-receptor inhibitor and neuroprotectant.

Aamir Aziz, BS, is a clinical research coordinator with Sierra Eye Associates in Reno, Nevada. Majid Khan, BS, and Noah Shafi, BS, are medical students at University of Nevada, Reno School of Medicine. Arshad M. Khanani, MD, MA, is a vitreoretinal surgeon, managing partner, director of clinical research, and director of fellowship at Sierra Eye Associates and a clinical associate professor at University of Nevada, Reno. Mr. Aziz, Khan, and Shafi report no related disclosures. Dr. Khanani reports consultancy to and research support from Graybug Vision. Reach Dr. Khanani at Editor’s note: This article is discussed in an episode of The Retina Podcast. Listen at .


Earlier rabbit studies showed that a smaller equivalent dosage of GB-102 produces ocular drug levels of sunitinib to support its potential use as a biannually administered injection (Figure 3). The rabbit studies also showed that 1 mg sunitinib is present at a relatively high concentration in the vitreous, retina, retinal pigment epithelium (RPE), and choroid through 6 months (Figure 3). In a mouse laser-injury choroidal neovascularization (CNV) model comparing a single intravitreal injection of either GB-102 or aflibercept, CNV suppression was observed in the GB-102 treated eyes through 6 months, whereas the suppressive effects from aflibercept were absent by month 2 (Figure 4), further supporting GB-102’s potential as a biannual treatment.

Figure 3. There is preclinical evidence of 6-month durability from a single intravitreal dose of GB-102. This plot shows the level of sunitinib in rabbit tissue after a single intravitreal injection of 1 mg GB-102.

Figure 4. There is preclinical evidence of 6-month durability from a single intravitreal dose of GB-102. This plot shows results from a mouse laser choroidal neovascularization model of a intravitreal injection of aflibercept vs GB-102.

Efforts to maximize the local concentration of therapeutic agents at target sites and minimize systemic exposure continue to be investigated. Studies in the pharmacokinetics of GB-102 demonstrate that over a 6-month period, singular intravitreal doses (0.2 mg or 1.0 mg) produce sunitinib levels of 10-fold (retina) and 1,000-fold (choroid/RPE) higher than the pharmacologically active threshold (~2 ng/mL) required for VEGFR inhibition.3 Additionally, plasma levels of free sunitinib following intravitreal injection have been undetectable.

More recent studies by other researchers aiming to increase residence time of sunitinib malate in the vitreous have incorporated encapsulated PLGA nanoparticles of sunitinib into thermoreversible gel. Evaluation of cellular uptake, wound scratch assay, and VEGF expression levels indicate that the sunitinib-loaded thermoreversible gel formulation produces greater uptake, increased antiangiogenic potential, and more prolonged inhibition of VEGF activity than sunitinib encapsulated PLGA nanoparticles alone.4 As such, successful development of sunitinib-loaded nanoparticle-based thermoreversible gel shows promise for use in the treatment of neovascular AMD.


The initial US phase 1/2a ADAGIO clinical trial evaluated safety and tolerability of GB-102 in 32 nAMD patients receiving current standard-of-care anti-VEGF agents.5 Patients were enrolled in the study if they showed previous positive response to anti-VEGF treatment. After enrolling in the study, patients had to show evidence of disease activity prior to the first and only injection of GB-102, which on average was a duration of 59.3 days after the last anti-VEGF treatment. The trial contained 4 groups — 0.25 mg, 0.5 mg, 1 mg, or 2 mg — as escalating-dose cohorts, and patients were followed for 8 months.

The ADAGIO trial met the primary endpoints of safety and tolerability, with no reported dose-limiting toxicities, drug-related serious adverse events, or cases of inflammation. Eighty-eight percent of patients were maintained on a single dose of GB-102 at 3 months, and 68% percent were maintained on a single dose of GB-102 at 6 months based on prespecified rescue criteria. Twenty-eight percent of patients had incomplete aggregation of GB-102 and had bioabsorbable particles enter the anterior chamber of the eye. This was self-limited and reversible with no long-term sequelae.

The incomplete aggregation led to optimization of GB-102 to reduce particle dispersion in the phase 2b ALTISSIMO clinical trial. This randomized study will compare 1 mg and 2 mg doses of GB-102 administered every 6 months to aflibercept every 2 months, with the objective to determine the optimal dose to evaluate in a global phase 3 program. The primary endpoint is time to first rescue injection through month 10. Secondary endpoints include changes in best-corrected visual acuity from patient baseline, changes in central subfield thickness from patient baseline, and number of injections, and the study will compare positive best-corrected visual acuity outcomes between GB-102 and aflibercept on their respective schedules.


GB-102 shows promise in a phase 1/2a study in improving treatment burden in most patients with nAMD. The benefits associated with a simple in-office injection every 6 months will offer favorable support for the use of GB-102 in the treatment of nAMD. The ongoing phase 2b ALTISSIMO study is evaluating safety and efficacy of GB-102 in patients with nAMD using a new optimized version of GB-102.6 Safety of the newly optimized GB-102 and rate of particle dispersion and migration in the anterior chamber, as well as rescue-free intervals for patients treated with GB-102, will be important in planning future global phase 3 registrational trials. RP


  1. Khanani AM, Skelly A, Bezlyak V, Griner R, Torres LR, Sagkriotis A. SIERRA-AMD: a retrospective, real-world evidence study of patients with neovascular age-related macular degeneration in the United States. Ophthalmol Retina. September 27, 2019. [Epub ahead of print]
  2. Semeraro F, Morescalchi F, Duse S, Parmeggiani F, Gambicorti E, Costagliola C. Afliber cept in wet AMD: specific role and optimal use. Drug Des Devel Ther. 2013;7:711-722.
  3. Peterson WM, Yang M. GB-102 for wet AMD: a novel injectable formulation that safely delivers active levels of sunitinib to the retina and RPE/choroid for over four months. Poster presented at: ARVO; 2016 May 1-5; Seattle, WA.
  4. Bhatt P, Narvekar P, Lalani R, Chougule MB, Pathak Y, Sutariya V. An in vitro assessment of thermo-reversible gel formulation containing sunitinib nanoparticles for neovascular age-related macular degeneration. AAPS PharmSciTech. 2019;20(7):281.
  5. Graybug Vision. Graybug vision presents top line results of phase 1/2a ADAGIO study at Hawaiian Eye & Retina 2019. Press release. Available at: .
  6. Graybug Vision. Graybug Vision initiates phase 2b (ALTISSIMO) clinical trial of GB-102 in patients with wet age-related macular degeneration. Press release. Available at: .